1. Field of the Disclosure
The disclosure generally relates to methods for preparing fluorinated vinyl ethers, and more particularly to methods for preparing fluoromethyl-1,1,3,3,3-pentafluoro-2-propenyl ether (sevoflurane compound A) and other vinyl ethers corresponding to fluorinated ether anesthetic compounds.
2. Brief Description of Related Technology
Certain fluorinated ethers are useful volatile anesthetic compounds, which can be administered via inhalation. Over time, such fluorinated ether anesthetic compounds can degrade and form corresponding vinyl ether degradation products/impurities. For example, sevoflurane, a widely-used volatile anesthetic compound, often includes an amount of fluoromethyl-1,1,3,3,3-pentafluoro-2-propenyl ether (“compound A”). Compound A has been shown to induce renal injury in rats and to produce transient renal injury in humans (Goldberg, et al., Anesth. Analg., 88:437-45 (1999)). Thus, it is desirable to ensure that the quantity of this vinyl ether is sufficiently low to ensure the quality of the anesthetic drug product. Similarly, it is desirable to ensure that the content of vinyl ether degradation products is below prescribed limits in other fluorinated ether-containing anesthetic compounds including but not limited to sevomethyl ether, chlorosevomethyl ether, isoflurane, desflurane, and difluoromethyl 2,2,2-trifluoroethyl ether. Typically, the amount of impurity in a sample of a fluorinated ether-containing anesthetic compound is determined by gas chromatography (GC) or other comparative spectroscopic technique using a pure reference standard. While compound A is commercially available, it is expensive. Additionally, vinyl ether compounds corresponding to other fluorinated ether-containing anesthetics are not commercially available. Accordingly, an efficient synthetic method to prepare fluorinated vinyl ether compounds is desirable.
Fluorinated ethers, however, are very reactive, and thus there are not many efficient methods for their synthesis. Huang, et al., J. Fluorine Chem., 45:239-253 (1989) describes the synthesis of compound A through the dehydrofluorination of sevoflurane using various bases. When sodium hydride with a triethylamine-boron complex was used as the base, no reaction occurred. Other bases such as potassium hydroxide, potassium tert-butoxide, sec-butyl lithium, tert-butyl lithium, phenyl lithium, and lithium diisopropylamide resulted in incomplete reactions with low yields when performed at −78° C. to 80° C. While a complete reaction was achieved using methyl lithium as the base at −78° C., Huang found the reaction to be unsuitable because it was difficult to isolate the desired vinyl ether product and the reaction was very exothermic and thus not capable of being scaled up even at the very low temperature of −78° C. As a result of these studies, Huang used lithium bis-(trimethylsilyl)amide as the base (observing product yields of 50-60% using preparative GC to isolate the material to the required purity). The disclosed method is not suitable for the large scale synthesis and isolation of sevoflurane compound A, however, because it is not practical to use preparative GC to isolate large quantities of product.
When lithium bis-(trimethylsilyl)amide was used to prepare the previously described vinyl ethers and fractional distillation was used to isolate the desired vinyl ether product, chemical conversion was not satisfactory and a laborious, repeated distillation process was necessary to achieve desired purity. The lengthy and cumbersome purification process was necessary because the crude product underwent further reactions with other components present in the reaction medium to generate difficult to remove side products. For example, as described in comparative example 1, the preparation of compound A using a 1.0 M solution of lithium bis -(trimethylsilyl)amide in THF as the base often required more than five months to obtain material with the desired 99% purity at a yield of only 10-20%.